Individuals with T cell acute lymphoblastic leukemia (T-ALL), a highly aggressive form of blood cancer that mostly affects children and adolescents, are commonly given prophylactic therapy to prevent spread of the disease to the central nervous system (CNS). Although such therapy markedly improves their chances for survival, it can also lead to substantial side effects. Noting that aberrant activation of the Notch1 signaling pathway is very common in T-ALL, Buonamici et al. developed two mouse models of T-ALL, both of which depended on the expression of oncogenic Notch1 (the intracellular Notch1 fragment, Notch1-IC) in hematopoietic progenitor cells. Mice in both models developed T-ALL, associated with infiltration of the CNS with leukemic cells. Gene expression profiling indicated that the chemokine receptor CCR7 was overexpressed in hematopoietic progenitor cells carrying fluorescently labeled Notch1-IC, an observation confirmed by real-time polymerase chain reaction, flow cytometry, and chemotaxis toward the chemokines CCL19 and CCL21. Cell surface CCR7 was present in 4 of 5 T-ALL lines and 8 of 11 samples of human primary T-ALL cells; moreover, its abundance in T-ALL lines decreased when Notch processing was inhibited. Human T-ALL cells carrying CCR7 infiltrated the CNS of recipient mice, whereas those lacking CCR7 did not. Similarly, Notch1-IC-hematopoietic progenitor cells from CCR7 knockout mice, unlike those from wild-type mice, did not infiltrate the CNS of wild-type recipients. Furthermore, Notch1-IC-hematopoietic progenitors failed to infiltrate the CNS of recipient mice that lacked CCL19. The authors conclude that the interaction between CCR7 and CCL19 is critical to CNS invasion by T-ALL and that CCR7 could provide a therapeutic target that might enable the use of CNS therapies with less severe side effects.
S. Buonamici, T. Trimarchi, M. G. Ruocco, L. Reavie, S. Cathelin, B. G. Mar, A. Klinakis, Y. Lukyanov, J.-C. Tseng, F. Sen, E. Gehrie, M. Li, E. Newcomb, J. Zavadil, D. Meruelo, M. Lipp, S. Ibrahim, A. Efstratiadis, D. Zagzag, J. S. Bromberg, M. L. Dustin, I. Aifantis, CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009). [PubMed]